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Cancer and embryonic development are closely related. The Clements laboratory uses zebrafish to investigate two major questions: What are the molecular and cellular components of the developmental specification niche for hematopoietic stem cells (HSCs)? How are normal signaling pathways co-opted during malignant transformation to induce cellular proliferation and migration—desirable processes when building an organism that can cause disease when activated in adult life?
We have recently shown that non-canonical Wnt signaling is critical for specification of HSCs during vertebrate development (Clements et al., Nature 2011). Wnt16 signaling appears to direct early formation of a vascular smooth muscle cell (VSMC) niche that induces HSC fate commitment from endothelial precursors in the primitive dorsal aorta. Strikingly, many of the Wnt signaling factors involved in this process are also aberrantly expressed in B cell leukemias. In the short term, we will define the downstream molecular factors and morphogenetic events governed by Wnt16 signaling that are responsible for specifying HSCs during development. In addition, we will determine how inappropriate activity of this pathway contributes to leukemia.
Our studies will inform long-term efforts to produce HSCs in vitro for regenerative medicine and transplantation therapies, while establishing a paradigm for using zebrafish to investigate whether and how candidate oncogenes contribute to transformation and cooperatively direct specific clinical progressions. Ultimately we seek to develop zebrafish disease models as a platform for cancer therapeutic studies and high throughput drug discovery.